This project has been utilizing O-15 and 18-FDG PET (positron emission tomography) in an attempt to map the underlying neural substrate of affective disorders. Using intravenous procaine as a relatively selective limbic activator, we have studied a large group of controls and mood disorder patients with O-15 PET in order to test the hypothesis of dysregulated limbic/paralimbic function in mood disorders. We have established a large data base of medication free O-15 and FDG PET studies in order to better define our heterogenous patient populations. Additionally we have begun to sequentially follow our patients through their treatment courses in order to assess significant cerebral blood flow (CBF) changes and their relationships to drug effects and clinical responses within individuals. Significant findings to date include: 1) Intravenous procaine significantly increases limbic/paralimbic rCBF in healthy volunteers; 2) Patients with mood disorders had lower baseline rCBF in the frontal lobes and blunted rCBF response to procaine; 3) In patients with mood disorder, carbamazepine responders as opposed to nonresponders, have baseline temporal hypermetabolism when compared to controls; 4) Nimodipine responders in comparison to controls had widespread baseline hypometabolism; 5) The degree of baseline frontal hypometabolism and severity of depression symptoms are inversely related; 6) In a relatively treatment naive population of unipolar patients, responders to pharmacotherapy in contrast to nonresponders have baseline prefrontal and anterior paralimbic hypometabolism. 7) We have demon- strated that medication free patients with a past history of unipolar depression continue to show anterior paralimbic hypometabolism. 8) Women healthy controls compared to men have increased basal ganglia, thalamic and anterior cingulate glucose metabolism; 9) CSF somatostatin correlates with cerebral metabolism in mood disorder patients; 10) We have demonstrated an inverse correlation between peripheral thyroid stimulating hormone and a positive correlation between total cholesterol and cerebral glucose metabolism. 11) Utilizing our large data base of healthy controls, we are using age-regression analysis to make use of individual patient data in treatment decisions.